Prostacyclin (PGI2) is a potent inhibitor of platelet aggregation and is a vasodilator. PGI2 (which is an enol ether) is too short- lived under physiological conditions to be useful as a drug, especially one to be administered orally. PGI2 is believed to be deactivated by hydrolysis of the enol ether functional group to give 6-keto-PGF1 alpha, a compound which has been shown to possess little or none of the therapeutic value of PGI2. Prostacyclin analogues of potential therapeutic value have been prepared, therefore, taking into account reasonable theories of this deactivation pathway, but none, so far, is as beneficial as PGI2. Synthetic limitations exist for increasing the scope of PGI2 analogues available. Herein we present new methodology for enol ether synthesis of use for the preparation for screening of prostacyclin analogues. These methods involve readily available starting materials and routes which are versatile in terms of the number of types of prostacyclin analogue precursors which can be prepared rapidly from common intermediates. In abiological chemical systems, hydrolysis of enol ethers can be slowed remarkably by attachment of electron- withdrawing groups to a double bond. The methods we propose herein enable the preparation of enol ether functionality in prostacyclin analogues by routes compatible with the placement of electron- withdrawing groups on the carbons associated with the enol ether double bond of the product. We propose to develop synthetic methodology to enable conversion of readily available prostacyclin precursors to stabilized prostacyclins. These routes are: (1) metal-assisted cyclization of acetylenic alcohols; (2) carbene complex equivalent - carbonyl coupling; (3) oxidative decarboxylation of beta- hydroxycarboxylates. We will also continue to study new routes for the synthesis of PGI2 precursors by the cyclization route. Prostacyclin analogues substituted at C-5 with electron- withdrawing groups will be prepared and tested for stability toward hydrolysis and will be substituted for screening for beneficial physiological activity.